Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT06AWU)

• DTT Name: Phosphodiesterase 3A (PDE3A)
• Synonyms: cGMP-inhibited 3',5'-cyclic phosphodiesterase A; Phosphodiesterase 3A; Cyclic GMP-inhibited phosphodiesterase A; Cyclic GMP inhibited phosphodiesterase A; CGI-PDE A
• Gene Name: PDE3A
• DTT Type: Successful target; [1]
• BioChemical Class: Phosphoric diester hydrolase
• UniProt ID: PDE3A_HUMAN
• TTD ID: T88975
• EC Number: EC 3.1.4.17
• Sequence:
  MAVPGDAARVRDKPVHSGVSQAPTAGRDCHHRADPASPRDSGCRGCWGDLVLQPLRSSRK
  LSSALCAGSLSFLLALLVRLVRGEVGCDLEQCKEAAAAEEEEAAPGAEGGVFPGPRGGAP
  GGGARLSPWLQPSALLFSLLCAFFWMGLYLLRAGVRLPLAVALLAACCGGEALVQIGLGV
  GEDHLLSLPAAGVVLSCLAAATWLVLRLRLGVLMIALTSAVRTVSLISLERFKVAWRPYL
  AYLAGVLGILLARYVEQILPQSAEAAPREHLGSQLIAGTKEDIPVFKRRRRSSSVVSAEM
  SGCSSKSHRRTSLPCIPREQLMGHSEWDHKRGPRGSQSSGTSITVDIAVMGEAHGLITDL
  LADPSLPPNVCTSLRAVSNLLSTQLTFQAIHKPRVNPVTSLSENYTCSDSEESSEKDKLA
  IPKRLRRSLPPGLLRRVSSTWTTTTSATGLPTLEPAPVRRDRSTSIKLQEAPSSSPDSWN
  NPVMMTLTKSRSFTSSYAISAANHVKAKKQSRPGALAKISPLSSPCSSPLQGTPASSLVS
  KISAVQFPESADTTAKQSLGSHRALTYTQSAPDLSPQILTPPVICSSCGRPYSQGNPADE
  PLERSGVATRTPSRTDDTAQVTSDYETNNNSDSSDIVQNEDETECLREPLRKASACSTYA
  PETMMFLDKPILAPEPLVMDNLDSIMEQLNTWNFPIFDLVENIGRKCGRILSQVSYRLFE
  DMGLFEAFKIPIREFMNYFHALEIGYRDIPYHNRIHATDVLHAVWYLTTQPIPGLSTVIN
  DHGSTSDSDSDSGFTHGHMGYVFSKTYNVTDDKYGCLSGNIPALELMALYVAAAMHDYDH
  PGRTNAFLVATSAPQAVLYNDRSVLENHHAAAAWNLFMSRPEYNFLINLDHVEFKHFRFL
  VIEAILATDLKKHFDFVAKFNGKVNDDVGIDWTNENDRLLVCQMCIKLADINGPAKCKEL
  HLQWTDGIVNEFYEQGDEEASLGLPISPFMDRSAPQLANLQESFISHIVGPLCNSYDSAG
  LMPGKWVEDSDESGDTDDPEEEEEEAPAPNEEETCENNESPKKKTFKRRKIYCQITQHLL
  QNHKMWKKVIEEEQRLAGIENQSLDQTPQSHSSEQIQAIKEEEEEKGKPRGEEIPTQKPD
  Q
• Function: Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminophylline	DML2NIB	Bronchial asthma	CA23	Approved	[2]
Anagrelide	DMSQ8MD	Thrombocythemia	3B63	Approved	[1]
Cilostazol	DMZMSCT	Intermittent claudication	BD40.00	Approved	[3]
Enoximone	DMQVZJD	Congestive heart failure	BD10	Approved	[4]
VESNARINONE	DMBKX3C	Cardiac failure	BD10-BD13	Approved	[5]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BEMORADAN	DMUL6GY	Heart failure	BD10-BD13	Phase 2	[6]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CI-930	DMADPQX	N. A.	N. A.	Discontinued in Phase 2	[7]
EMD-53998	DMVS8IE	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 1	[6]
BMY-20844	DMDPJ8M	N. A.	N. A.	Terminated	[8]
IMAZODAN	DMWTFO3	N. A.	N. A.	Terminated	[9]
LAS-31180	DMW2K1L	Heart failure	BD10-BD13	Terminated	[10]

26 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,3,9,9a-Tetrahydro-imidazo[4,5-b]quinolin-2-one	DM7U31Q	Discovery agent	N.A.	Investigative	[11]
1,3-Dihydro-imidazo[4,5-b]quinolin-2-one	DMB9XR5	Discovery agent	N.A.	Investigative	[11]
1,3-Dihydro-naphtho[2,3-d]imidazol-2-one	DM8CYOP	Discovery agent	N.A.	Investigative	[11]
1,5-Dihydro-imidazo[2,1-b]quinazolin-2-one	DMYA25G	Discovery agent	N.A.	Investigative	[12]
2-Morpholin-4-yl-8-phenylethynyl-chromen-4-one	DMNKHOI	Discovery agent	N.A.	Investigative	[13]
2-morpholino-7-(2-phenylethynyl)-4H-chromen-4-one	DM4XKYN	Discovery agent	N.A.	Investigative	[13]
2-morpholino-7-phenyl-4H-chromen-4-one	DMK7WON	Discovery agent	N.A.	Investigative	[13]
5-Methyl-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DM0E1Y9	Discovery agent	N.A.	Investigative	[11]
6-(2-Imidazol-1-yl-vinyl)-1H-quinolin-2-one	DMXZWOA	Discovery agent	N.A.	Investigative	[9]
6-Imidazol-1-yl-3,4-dihydro-1H-quinolin-2-one	DMRMSU5	Discovery agent	N.A.	Investigative	[9]
6-Pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one	DMG5ABT	Discovery agent	N.A.	Investigative	[9]
7-Chloro-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DMWUS5Q	Discovery agent	N.A.	Investigative	[11]
7-Ethoxy-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DMI16MD	Discovery agent	N.A.	Investigative	[11]
7-Fluoro-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DMNRCDI	Discovery agent	N.A.	Investigative	[11]
7-Iodo-1,5-dihydro-imidazo[2,1-b]quinazolin-2-one	DM6K5NF	Discovery agent	N.A.	Investigative	[12]
7-Methyl-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DM5EQJU	Discovery agent	N.A.	Investigative	[11]
8-Chloro-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DM5IGOL	Discovery agent	N.A.	Investigative	[11]
8-Methyl-1,3-dihydro-imidazo[4,5-b]quinolin-2-one	DM92XPO	Discovery agent	N.A.	Investigative	[11]
8-methyl-2-morpholino-7-phenoxy-4H-chromen-4-one	DMWZ27A	Discovery agent	N.A.	Investigative	[13]
8-methyl-2-morpholino-7-phenyl-4H-chromen-4-one	DMUI1YZ	Discovery agent	N.A.	Investigative	[13]
BENZOYLENUREA	DMY5O1U	Discovery agent	N.A.	Investigative	[14]
isobutylmethylxanthine	DM46F5X	Discovery agent	N.A.	Investigative	[3]
KURAIDIN	DMLDUJ1	Discovery agent	N.A.	Investigative	[15]
KURARINOL	DMRV5YE	Discovery agent	N.A.	Investigative	[15]
SOPHOFLAVESCENOL	DM8Y1S7	Discovery agent	N.A.	Investigative	[15]
TETRAHYDROBENXIMIDAZOLE	DMNURE0	Discovery agent	N.A.	Investigative	[7]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	8.06E-01	-0.04	-0.15
Thrombocythemia	3B64	Whole blood	3.33E-01	1.35E-02	0.14
Coronary artery disease	BA80-BA8Z	Peripheral blood	1.33E-01	-0.04	-0.38
Chronic obstructive pulmonary disease	CA23	Lung tissue	1.18E-01	0.12	0.48
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	6.10E-01	-0.05	-0.16

References

• [1] Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45.
• [2] Topical fat reduction from the waist. Diabetes Obes Metab. 2007 May;9(3):300-3.
• [3] A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem. 1985 May;28(5):537-45.
• [4] Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin... J Med Chem. 1987 Feb;30(2):303-18.
• [5] Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors. Bioorg Med Chem. 2010 Jan 15;18(2):855-62.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazi... J Med Chem. 1989 Feb;32(2):342-50.
• [8] Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility. J Med Chem. 1992 Jul 10;35(14):2688-96.
• [9] 3,4-Dihydroquinolin-2(1H)-ones as combined inhibitors of thromboxane A2 synthase and cAMP phosphodiesterase. J Med Chem. 1992 Feb 21;35(4):620-8.
• [10] Pharmacological profile of LAS 31180, a new inotropic/vasodilator quinolone derivative. Arzneimittelforschung. 2000 Nov;50(11):980-6.
• [11] 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation. J Med Chem. 1991 Sep;34(9):2906-16.
• [12] Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoim... J Med Chem. 1988 Nov;31(11):2136-45.
• [13] Analysis of anti-PDE3 activity of 2-morpholinochromone derivatives reveals multiple mechanisms of anti-platelet activity. Bioorg Med Chem Lett. 2006 Feb 15;16(4):969-73.
• [14] CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors as an application example. Eur J Med Chem. 2008 Jul;43(7):1349-59.
• [15] A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. Bioorg Med Chem Lett. 2002 Sep 2;12(17):2313-6.